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Microgravity-induced endothelial inflammation contributes to cardiovascular dysfunction in astronauts, but the metabolic mechanisms involved are not fully defined. Sirtuin-3 (SIRT3), a mitochondrial deacetylase, regulates cellular metabolism and redox balance. The results demonstrate that two-dimensional clinorotation-induced simulated microgravity suppresses SIRT3 in human umbilical vein endothelial cells (HUVECs), resulting in mitochondrial dysfunction, NLRP3 inflammasome activation, and pyroptosis. SIRT3 overexpression mitigated these effects, while SIRT3 knockdown exacerbated them. Mechanistically, SIRT3 deletion promoted acetylation of pyruvate dehydrogenase E1α (PDHA1) at lysine 83, inhibiting pyruvate dehydrogenase complex (PDHC) activity and shifting metabolism toward higher levels of glycolysis. PDHA1 transfection suppressed NLRP3 inflammasome activation, pyroptosis, and glycolysis in HUVECs under simulated microgravity, while restoring mitochondrial membrane potential (ΔΨm) and oxidative phosphorylation. The PDHA1-K83R mutant provided stronger protection than wild-type PDHA1. These findings reveal that the SIRT3-PDHA1 axis links mitochondrial metabolism to endothelial inflammation under simulated microgravity, suggesting that targeting this pathway could help maintain vascular health during spaceflight.